The inability of the host to eliminate cancer cells remains a major problem. Although an increasing number of therapeutic monoclonal antibodies have been approved for treatment of various cancers, emergence of resistance to these antibodies is frequently observed, given the many different molecular pathways underlying cancer growth and progression to metastasis. Although the immune system is the principal mechanism of cancer prevention, cancer cells counteract immune surveillance. Therefore, there exists a need for improved therapeutic binding antagonists or antibodies and methods of treating cancer and chronic viral infections with such reagents.